Synthesis and crystal structure of N-(5-acetyl-4-methylpyrimidin-2-yl)benzenesulfonamide

N-(5-Acetyl-4-methylpyrimidin-2-yl)benzenesulfonamide was synthesized and structurally characterized. In the crystal, π–π interactions between the phenyl and pyrimidine groups of neighbouring molecules form molecular chains parallel to [010]. Adjacent chains are linked by N—H⋯N hydrogen-bonding interactions, resulting in a three-dimensional network.


Chemical context
Sulfonamide-bearing molecules with one or several pharmacological scaffolds constitute a class of drugs with antiviral, anticancer, anti-carbonic anhydrase (CA), diuretic, cyclooxigenase 2 (COX2) inhibitory, protease inhibitory, and/or antibacterial activities (Supuran, 2003;Scozzafava et al., 2003;Casini & Scozzafava, 2002). It is noteworthy that the sulfonamide moiety is one of the significant, privileged building blocks that medicinal chemists frequently find in potent drugs . Thus, many widely marketed drugs incorporate this moiety. Several pyrimidine sulfonamides and other pyrimidine analogues that could be incorporated in new designs for bioactive molecules with medicinal applications have already been considered (Azzam, 2019;Azzam et al., 2017Mohamed-Ezzat et al., 2021, 2022Elgemeie et al., 2015aElgemeie et al., ,b, 2017. The synthesis of N-(5-acetyl-4-methylpyrimidin-2-yl)benzenesulfonamide (AMBS) was reported several decades ago (Gutsche et al., 1964). In this article, we describe an alternative novel one-pot reaction methodology for the synthesis of this compound, which was also crystallized and crystallographically investigated.

Structural commentary
N-(5-Acetyl-4-methylpyrimidin-2-yl)benzenesulfonamide (AMBS) crystallizes in the monoclinic system, space group P2 1 /c and contains four molecules in the unit cell (Z = 4). The asymmetric unit is shown in Fig. 1. The acetaldehyde group of the molecule is disordered with two components related by a twist of 31.3 (1) about the C ar -C bond. Apart from a slight twist of the aldehyde group associated with the disorder, the 1-(2-amino-4-methylpyrimidin-5-yl)ethan-1-one segment of the molecule is essentially planar, the sulfonamide atom S1 being located only 0.423 (1) Å away from the plane of the pyrimidine group. The molecule exhibits a C7-N1-S1-C1 torsion angle of À79.0 (2) , while the twist between the planes of the phenyl group and the pyrimidine ring comprises a dihedral angle of 63.07 (7) .

Supramolecular features
The packing of AMBS is shown in Fig. 2. In the crystal, partial overlap is observed between the phenyl group of one molecule and the pyrimidine group of an adjacent one related by 2 1 symmetry (1 À x, À 1 2 + y, 1 2 À z or 1 À x, 1 2 + y, 1 2 À z). The dihedral angle between the planes of the rings is 9.04 (10) with a ring centroid-to-centroid distance of 3.769 (1) Å (Fig. 3). The slippage distances between the overlapping rings are 1.44 Å (1 À x, À 1 2 + y, 1 2 À z) and 1.58 Å (1 À x, 1 2 + y, 1 2 À z). Theseinteractions form chains in the structure in which one AMBS molecule comprises the linker between two further molecules. The bent nature of the molecule results in a zigzag pattern of chains propagating parallel to [010].
The hydrogen-bonding interactions in the crystal are summarized in Table 1. Two linear N-HÁ Á ÁN hydrogen bonds, with NÁ Á ÁN distances of 2.891 (2) Å , occur between two neighbouring molecules related by inversion symmetry (1 À x, 1 À y, 1 À z). A pair of hydrogen bonds is formed between the pyrimidine and amine groups of the two molecules, resulting in a R 2 2 (8) geometry (Fig. 2). The hydrogen bonds link the molecular chains formed by theinteractions and are perpendicular to the chains' protrusion. Additionally, nonclassical hydrogen-bonding contacts of the C-HÁ Á ÁO type with CÁ Á ÁO distances in the range of ca 2.7-3.4 Å help to consolidate the structure.

Database survey
A survey of the Cambridge Structural Database (Groom et al., 2016;accessed February 2023) using CONQUEST (Bruno et al., 2002) for structures containing the N-(pyrimidin-2yl)benzenesulfonamide group gave 164 hits, i.e. too many for them all to be analysed in detail.
An example of a closely related compound is 4,5,6-trimethyl-2-[(phenylsulfonyl)amino]pyrimidine (TPAP) (refcode VENKIJ; Li & Yang, 2006). In this structure, the dihedral angle between the planes through the phenyl and pyrimidine rings is 91.9 , larger than that observed for the title compound AMBS [63.07 (7) ]. In contrast to AMBS,interactions are only observed between the pyrimidine rings in TPAP, resulting in stacking along the a-axis with interplanar distances of 3.81 Å .     Table 1 Hydrogen-bond geometry (Å , ).

Figure 1
The molecular structure of the title compound with atom labels and 50% probability atomic displacement ellipsoids.
Another closely related compound is N-(pyrimidin-2yl)benzenesulfonamide (PBS) (refcode XIFKAZ01; Coles et al., 2000). In PBS, the dihedral angle between the planes through the phenyl and pyrimidine rings is 74.5 , again larger than for AMBS. Also unlike in AMBS,interactions occur in PBS between pairs of molecules involving only the pyrimidine rings and with an interplanar distance of 3.5 Å . Similarly to AMBS, two linear N-HÁ Á ÁN hydrogen bonds are observed in PBS between the pyrimidine and amine groups of neighbouring molecules, resulting in similar R 2 2 (8) motifs.

Synthesis and crystallization
Phenylsulfonyl guanidine 1 is a common starting material for the synthesis of several heterocyclic compounds and has been utilized effectively in the generation of a range of biologically active compounds. Our approach was based on synthesizing the substituted sulfonyl derivative 4 by reacting the sulfonyl guanidine 1 with triethylorthoformate 2 and acetyl acetone 3 (Fig. 4). The target product was identified by NMR spectroscopy and X-ray crystallography. Synthesis of compound 4: Triethylorthoformate (5 ml) was added to a mixture of phenylsulfonyl guanidine (0.05 mol) and acetyl acetone (0.1 mol). The reaction mixture was then refluxed for 6 h. After cooling, the resulting precipitate was filtered and crystallized from ethanol.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The N-H hydrogen was refined freely. The remaining hydrogen atoms were positioned geometrically and using a riding model [C-H = 0.93-0.96 Å with U iso (H) = 1.2 or 1.5 U eq (C). The acetaldehyde group of the molecule is disordered with two components related by a twist of 31.3 (1) about the C ar -C bond. In the refinement, the two components were restrained to have similar geometry (SAME in SHELXL) and atomic displacement parameters (SIMU and ISOR). The occupancies of the two components refined to 0.591 (11)/0.409 (11).

Funding information
We thank Helwan University for funding this research.

N-(5-Acetyl-4-methylpyrimidin-2-yl)benzenesulfonamide
Crystal data Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.